# TRPC3 and TRPC6: Multimodal Cation-Conducting Channels Regulating Cardiovascular Contractility and Remodeling

## TL;DR

This paper reviews how TRPC3 and TRPC6 channels regulate heart function and could be important for developing new treatments.

## Contribution

The paper provides a comprehensive overview of the diverse activation mechanisms and roles of TRPC3 and TRPC6 channels in cardiovascular health and disease.

## Key findings

- TRPC3 and TRPC6 channels are activated by multiple mechanisms beyond DAG, influencing heart function.
- Recent studies have clarified the structural and functional properties of these channels.
- TRPC3 and TRPC6 are emerging as potential therapeutic targets for cardiovascular diseases.

## Abstract

Transient receptor potential canonical (TRPC) channels function as multimodal cation channels that integrate chemical and mechanical cues to regulate cellular signaling. Among them, TRPC3 and TRPC6 have been studied primarily in the context of cardiovascular and renal physiology, and their roles in other organ systems are now increasingly recognized. Although these channels are known to be activated downstream of phospholipase C (PLC) signaling, especially 1,2-diacylglycerol (DAG) production, their precise modes of activation under native physiological conditions remain incompletely understood. Recent structural and functional studies have greatly advanced our understanding of their primary activation by DAG. This review summarizes how decades of physiological analyses have revealed multiple modes of TRPC3 and TRPC6 channel activation beyond DAG gating, providing a broader perspective on their diverse regulatory mechanisms. This review also highlights recent progress in elucidating the channel properties, activation mechanisms, and the physiological as well as pathophysiological roles of TRPC3 and TRPC6 in cardiovascular contractility and remodeling, and discusses the remaining challenges that will lead to the establishment of TRPC3 and TRPC6 as validated therapeutic targets.